Monomenthyl esters of dicarboxylic acids such as monomenthyl succinate (MMS), monomenthyl glutarate (MMG), and monomenthyl adipate (MMA) are physiological cooling agents used in flavors, oral care and cosmetics. When prepared using l-menthol as a starting material, these half acid esters have the structures indicated below:
The use of these compounds as flavoring or physiological cooling agents is discussed, for example, in U.S. Pat. Nos. 5,725,865 (MMS) and 6,884,906 (MMA), and Smith et al., Food Tech. 55 (2001) 53 (MMG). Additionally, MMS and MMG have achieved FEMA GRAS (generally recognized as safe) status.
Despite the unquestionable value of the monomenthyl esters, relatively little is known about how to make them efficiently. In one approach (see Rule et al., J. Chem. Soc. (1928) 1347 and Hilditch et al., J. Chem. Soc. (1909) 1570), the corresponding dicarboxylic acid (e.g., succinic acid) is first reacted with an excess of thionyl chloride. Reaction of the chlorinated intermediate with excess menthol (100° C., 5-6 hours) provides a bis-menthyl ester. Finally, the bis-menthyl ester is partially hydrolyzed using sodium dissolved in 95% ethanol, and the desired monomenthyl ester is isolated in a tedious extractive workup.
The monomenthyl esters can also be made by reacting menthol with the corresponding saturated anhydride as follows:
A few publications teach to simply heat equimolar amounts of menthol and the anhydride together in the absence of a solvent or catalyst at 110-120° C. for about one day (see, e.g., Jabloner et al., J. Polym. Sci. A., 18 (1980) 2933), but none provides information about yields or selectivities to the monomenthyl ester.
U.S. Pat. No. 3,111,127 teaches a preparation of MMS from the reaction of menthol and succinic acid either uncatalyzed in refluxing chloroform, or catalyzed by p-toluenesulfonic acid in refluxing toluene. It is unclear whether the monomenthyl ester can be made efficiently by these methods, and solvents are preferably avoided for making compounds to be used in flavor or fragrance applications.
More recently, Shimizu et al. (Synlett (1995) 650) published a process for selectively making monomenthyl esters by using a large excess of the anhydride. Reaction of three moles of succinic anhydride with one mole of menthol in pyridine solvent in the presence of one equivalent of dimethylaminopyridine (DMAP) gave MMS in 90-97% yield. Unfortunately, the method is impractical because it requires a large excess of the anhydride, pyridine solvent, and the highly toxic DMAP.
In sum, an efficient, practical way to make monomenthyl esters of dicarboxylic acids is needed. In particular, a process that provides high selectivity to the monomenthyl ester is essential. Ideally, the process would avoid solvents or other toxic reagents and would be simple to practice.